Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding
Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding
Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here, we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.
Furniss, R. Christopher D.
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Kadeřábková, Nikol
be047d52-4d76-412e-b649-68eed98634d7
Barker, Declan
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Mccarthy, Ronan
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22 February 2022
Furniss, R. Christopher D.
7932dd03-6b2f-4d11-9570-7cfbbc5284e5
Kadeřábková, Nikol
be047d52-4d76-412e-b649-68eed98634d7
Barker, Declan
df018031-4222-4cb3-967d-f21675994791
Mccarthy, Ronan
0b2cf2e0-b0ff-4c92-aa04-92d91182d1f2
Furniss, R. Christopher D., Kadeřábková, Nikol and Barker, Declan
,
et al.
(2022)
Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding.
eLife, 11.
(doi:10.7554/elife.57974).
Abstract
Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here, we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.
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elife-57974-v2
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Accepted/In Press date: 11 January 2022
e-pub ahead of print date: 13 January 2022
Published date: 22 February 2022
Identifiers
Local EPrints ID: 508244
URI: http://eprints.soton.ac.uk/id/eprint/508244
ISSN: 2050-084X
PURE UUID: edbf059f-0e27-4dbe-b9b6-8230d2872e3d
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Date deposited: 15 Jan 2026 17:37
Last modified: 16 Jan 2026 03:13
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Contributors
Author:
R. Christopher D. Furniss
Author:
Nikol Kadeřábková
Author:
Declan Barker
Author:
Ronan Mccarthy
Corporate Author: et al.
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